Within the description which follows various publications are referenced by arabic numerals. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
In 1978, Gold, Redmond and Kleber demonstrated that clonidine diminished the opiate withdrawal syndrome in chronically addicted human subjects (1). Clonidine is a presynaptic alpha-2 noradrenergic agonist. Central noradrenergic function had previously been implicated in the action of opiates without anatomical specificity since the 1960's (2, 3). By the mid-1970's, evidence accumulated indicating that a major anatomical connection between the central adrenergic and opiate systems existed in a small nucleus of the dorsal pons, the locus coeruleus. This nucleus accounts for nearly half of the noradrenergic neurons and produces the majority of norepinephrine in the mammalian brain (4). These adrenergic cells are densely populated with opiate receptors (5), and either enkaphalins (6, 7) or opiates (8, 9) and alpha-2 adrenergic agonists (10, 11) decreased their firing rate. Opiate withdrawal results in a marked increase in this firing rate (12). Extensive data has now accumulated in both animals (13, 14, 15, 16) and man (17, 18, 19, 20) confirming Gold's observation that clonidine diminishes opiate withdrawal syndromes and that the diminished withdrawal behavior is related to the diminished firing rate in the adrenergic neurons (21). The present invention relates to the discovery that alpha-2 adrenergic agonists such as clonidine markedly alter the acute withdrawal syndrome associated with cigarette smoking and suggests that central adrenergic overactivity is a common feature in the pathophysiology of withdrawal syndromes seen with cigarettes, alcohol and opiates. The invention also relates to the discovery that such withdrawal symptoms may be prevented by alprazolam.